Consent

Objectives

Test the safety and efficacy of injecting mesenchymal precursor cells during implantation of a left ventricular assist device.

Background

Heart failure is a condition where the heart muscle can no longer meet the oxygen demands of the body. In an attempt to preserve cardiac output, gradual cardiac remodeling occurs in the form of changes to the size, shape, and function of the heart. Eventually these changes weaken the heart and lead to a deterioration of left ventricular contractility. People diagnosed with advanced heart failure typically require a heart transplant or surgically implanted left ventricular assist device (LVAD). An LVAD is a pump that redirects blood from the left ventricle and moves it to the aorta. For people with a possibility of heart failure reversal, the LVAD can be removed if they show signs of recovery such as an improved ejection fraction and reverse remodeling. Because reverse remodeling is often not sufficient to remove the device, preliminary findings indicate that the administration of stem cells or allogeneic mesenchymal precursor cells (MPCs) during implantation of the LVAD, may contribute to ventricular recovery. Injections of MPCs are correlated with increased numbers of cardiomyocytes and myocardial blood vessels, but their use during LVAD implantation needed closer examination.

Subjects

Adult subjects with end-stage cardiac failure could enroll in this study if they had a clinical indication for implantation of an LVAD. They could not participate if they had a prior cardiac transplantation or were scheduled to receive a percutaneous LVAD. Exclusion criteria also included: history of a stroke, myocardial infarction, or receipt of cardiothoracic surgery within 30 days prior to randomization. Participants with a history of LV reduction surgery or cardiomyoplasty were also ineligible for the study as were those with a low platelet count or an active systemic infection.

Design

There were 11 participating centers located throughout the United States and of the 47 eligible participants, 20 were randomized to receive an injection of 25 million allogenic MPCs and 10 were randomized to receive a control substance of cryoprotective medium (50% Alpha modified Eagle’s medium/42.5% ProFreeze NAO freezing medium/7.5% dimethyl sulfoxide) at the time of LVAD implantation. The MPCs were TRO-3 immuno-selected, culture-expanded, immature sub-fraction of adult bone marrow-derived mononuclear cells and were cryopreserved until use. Tests for transmissible infectious diseases, karyotype, tumorigenicity, sterility, endotoxins, and mycoplasma were performed. The implanted HeartMate II LVAD was programmed to run at full support.

The secondary endpoint of efficacy was designed to measure how well participants tolerated 30 minutes of weaning from the LVAD. During weaning attempts, the LVAD was programmed to run at the low-speed of 6000 rpm and participants were observed for signs and symptoms of hypoperfusion such as dyspnea, fatigue, chest pain, or pulmonary edema. Patients who successfully tolerated the first 20 minutes of weaning were then asked to perform a 6 minute walk (6MW). Those who were able to complete the 6MW were assessed for changes in myocardial size and function using an echocardiogram. Assessments were measured at 30, 60, and 90 days after randomization and then every 60 days until cardiac transplantation or 12 months, whichever came first.

Conclusions

The study demonstrated that administering MPCs during the implantation of an LVAD was safe as no patients had an adverse primary event within 90 days after randomization or during the 12-month follow-up. For efficacy, 50% of participants in the MPC group tolerated weaning at 90 days as compared to 20% of participants in the control group. These promising results indicate that further research would help establish if higher or additional doses of MPCs would help more participants have better outcomes. Further research is also indicated as this was a small study and successful weaning was influenced by participant comorbidities.

Resources Available

Study Documents

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